Gut microbiota and <i>Lactobacillus</i> species maintain the small intestine stem cell niche and ameliorate the severity of necrotizing enterocolitis
Authors: Tereza Svabova, Anna Jelinkova, Umesh Kumar Gautam
Journal: Allergy (2023)

The microbiota plays an undisputed role in mammalian development and physiology. It enhances energy extraction from ingested food, protects against harmful pathogens, regulates immune function, and strengthens biochemical signaling. In mammals, including humans, colonization of the gut by microbes begins at birth,1 and several recent studies have shown that the microbiome contributes to postnatal host development in early childhood. In this sense, microbial dysbiosis in infancy has been associated with certain diseases such as inflammatory bowel disease, cardiometabolic disorders, cancer, and neuropsychiatric disorders.2 The intestinal epithelial cells (IECs) are in direct contact with a large number of bacteria and the external environment, forming a barrier between inside and outside while fulfilling a critical role in the absorption of nutrients. The small intestine crypt-villus architecture is a unique structure that provides a microenvironment in which intestinal stem cells (ISCs) differentiate into a variety of different epithelial subtypes. These subtypes include enterocytes, also known as IECs, Paneth cells, goblet cells, enteroendocrine cells, tuft cells, and microfold cells (M cells).3 Kim et al. demonstrated that early-life gut microbiota exposure promotes the differentiation of ISCs into Paneth cells by regulating numbers of CD206+ macrophages associated with epithelial Wnt signaling, which maintains mesenchymal niche cell proliferation (Figure 1). They suggested that the maintenance of this stem cell niche is critical for small intestinal homeostasis and its disruption by antibiotic (ATB) administration can lead to inflammatory conditions, which can manifest as necrotizing enterocolitis (NEC). NEC is a severe inflammatory disease affecting the small intestine, especially in preterm infants, and is the leading cause of death in this group. To investigate the role of the microbiota and ISC differentiation in the pathogenesis of NEC, Kim et al. induced NEC-like phenotypes in neonatal mice by exposing them to hypoxia and gavage feeding of hyperosmolar formula and LPS. ATB-induced dysbiosis resulted in further impaired stem cell niche in the small intestine and led to severe NEC manifestation. They also confirmed previous findings that microbial dysbiosis in NEC is associated with an increased abundance of Proteobacteria and a concomitant underrepresentation of Firmicutes and Lactobacillus.4 To determine whether members of genus Lactobacillus affect Paneth cell formation during NEC onset, Kim et al. treated pregnant female mice and their pups with selected Lacticaseibacillus rhamnosus (Lr) strain in the presence or absence of NEC-inducing experimental conditions. They found that Lr transplantation corrected the impaired development of the mesenchymal niche and Paneth cell differentiation and consequently partially rescued the NEC-like phenotypes (Figure 1).4 Previous studies in germ-free mice and mice with Toll-like receptor knockout have highlighted the key relationship between the microbiome and NEC development.5 Probiotic administration has been suggested as a potential strategy to prevent NEC. In general, probiotic bacteria, including Lactobacillus species, modulate microbiota composition, intestinal epithelial barrier function, and cytokine secretion. Kim et al. showed that transplantation of Lr restored the amount of Lactobacilli resulting in an improvement of NEC-like phenotypes. We have recently shown that administration of Lactiplantibacillus plantarum WJL also increased the proliferation of intestinal epithelial stem cells in chronically undernourished juvenile mice, resulting in improved growth of the young. This effect was strictly bacterial strain-dependent, and NOD2 signaling in IECs was essential for the bacteria-mediated beneficial effect.6 A growing body of evidence suggests that the strain specificity of probiotic microbes and their efficacy in alleviating specific diseases are crucial aspects that are often overlooked when selecting the best probiotic microbes.7 Therefore, it would be important to determine whether all probiotic bacterial species or even different Lr strains promote the stem cell niche development by the same mechanism. Further, as it has been shown that NOD2 signaling plays a crucial role in epithelial stem cell proliferation, the role of this receptor in the NEC prevention and development should be probed. In addition to the already mentioned importance of probiotic strain specificity, there are several other aspects (such as complex probiotic-microbiota interactions, individual probiotic variability and safety, lack of protocol standardization, and limited clinical evidence) that need to be rigorously addressed before any probiotic bacteria could be used in human disease therapy.8 To sum up, the study by Kim et al. provides another important contribution to the understanding of the mechanism of NEC pathogenesis. However, more research is needed to fully understand the role of Lactobacilli and other probiotic bacteria in the prevention of NEC and to strengthen their potential as therapeutic agents to combat this serious disease. The authors would like to thank Dr. Anna Globinska for figure design. The authors have no conflict of interest to declare. TS is supported by a grant from Czech Health Research Council (NU20-05-00038). UKG and AJ are supported by the JUNIOR STAR grant from the Czech Science Foundation (GACR 21-19640M).